Alzheimer's disease (AD) is the most common cause of dementia affecting older people. An estimated 4.5 million Americans and nearly 28 million people globally, a number that is predicted to rise sharply as the world population continues to age, are afflicted with AD. The estimate of the worldwide costs for AD dementia care is approximately $248 billion.
The formation of extracellular insoluble amyloid plaques of the β-amyloid peptide (Aβ) is regarded as the central common factor for the pathogenesis of AD. However, the accumulation of amyloid deposits is also an ever-present event in the aging brain, whether demented or not. One factor that distinguishes plaques present in AD is their ability to produce neuritic degeneration and neurofibrillary tangles (McKee et al. (1991) Ann. Neurol., 30:156-165; Arriagada et al. (1992) Neurology, 42:631-639; Cummings et al. (1996) Neurobiol. Aging, 17:921-933; Knopman et al. (2003) J. Neuropathol. Exp. Neurol., 62:1087-1095). Moreover, while the neuritic process itself is not yet fully understood, the frequency of neuritic plaques in the cerebral cortex shows a strong relationship with the severity of dementia. Biochemical investigations also suggest that companion molecule(s) associated with amyloid plaques facilitate the transformation of these plaques to their degenerative form. One such companion molecule is butyrylcholinesterase (BChE) (Lahiri et al. (2004) Curr. Pharm. Des., 10:3111-9; Lahiri et al. (2003) Curr. Drug Targets, 4:97-112; Giacobini et al. (2002) J. Neural. Transm., 109:1053-65; Layer, P. G. (1995) Alzheimer Dis. Assoc. Disord., 9 Suppl 2:29-36; Perry et al. (1978) Neuropathol. Appl. Neurobiol., 4:273-7; Perry et al. (1980) Age Ageing., 9:9-16; Guillozet et al. (1997) Ann. Neurol., 42:909-18; Mesulam et al. (1994) Ann. Neurol., 36:722-7).
Several lines of evidence suggest that BChE, possibly through its own proteolytic activity or in association with heparin sulfate proteoglycans, plays a role in the aggregation and consolidation processes taking place at the early stages of the plaque formation. Mesulam et al. (Guillozet et al. (1997) Ann. Neurol., 42:909-18; Mesulam et al. (1994) Ann. Neurol., 36:722-7) and others (Moran et al. (1993) Acta Neuropathol. (Berl)., 85:362-9) have shown that BChE is present in key brain areas and appears to contribute to the maturation of plaques in AD. BChE co-localization within the amyloid plaques correlates with the conversion of benign plaques to form pathogenic structures associated with neuritic degeneration and dementia. BChE becomes associated with amyloid plaques at approximately the same time that the Aβ deposits assume a compact β-pleated conformation. BChE appears to participate in the change of these plaques from an initially benign form to a malignant form characterized by the neuronal loss and clinical dementia.
Among the earliest and most consistently reported observations in AD brains are profound reduction in the activity of acetylcholinesterase (AChE) and the relationship of AChE levels to the severity of dementia (Schliebs et al. (2006) J. Neur. Trans., 113:1625-44; Francis et al. (1999) J. Neurol. Neurosurg. Psych., 66:137-47; Davies et al. (1976) Lancet, 2:1403; Coyle et al. (1983) Science, 219:1184-1190). The cholinergic hypothesis, which first emerged more than 20 years ago (Davies et al. (1976) Lancet, 2:1403), proposes that dementia, as well as the memory loss and decrease of cognitive functions in AD are caused by diminishing levels of acetylcholine in the brain. While AChE and its inhibition has long been an accepted focal point to therapeutic interventions in AD and a target of radiotracers for mapping acetylcholinesterase in human brain using PET and SPECT (Irie et al. (1996) J. Nucl. Med., 37:649-655; Kilbourn et al. (1996) Synapse, 22:123-131; Kuhl et al. (1996) J. Nucl. Med., 37:21P; Iyo et al. (1997) Lancet, 349:1805-1809; Bencherif et al. (2002) Synapse, 45:1-9; Reed et al. (1999) Neurology, 52:680-682; Herholz et al. (2000) J. Neural Transm., 107:1457-68; Snyder et al. (2001) J. Cereb. Blood Flow Metab., 21:132-43; Brown-Proctor et al. (1999) Nucl. Med. Biol., 26:99-103), BChE emerged only recently as an important contributor to the occurrence, symptoms, progression and responses to treatment in AD (Lahiri et al. (2004) Curr. Pharm. Des., 10:3111-9; Lahiri et al. (2003) Curr. Drug Targets, 4:97-112; Giacobini et al. (2002) J. Neural. Transm., 109:1053-65; Layer, P. G. (1995) Alzheimer Dis. Assoc. Disord., 9 Suppl 2:29-36; Perry et al. (1978) Neuropathol. Appl. Neurobiol., 4:273-7; Perry et al. (1980) Age Ageing., 9:9-16; Guillozet et al. (1997) Ann. Neurol., 42:909-18; Mesulam et al. (1994) Ann. Neurol., 36:722-7; Namba et al. (1999) Eur. J. Nucl. Med., 26:135-43; Arendt et al. (1992) Neurochem. Int., 21:381-96). Guillozet et al. (Guillozet et al. (1997) Ann. Neurol., 42:909-18) found that although the Aβ plaques are present in brains of demented and normal individuals, the plaques positive for BChE are found only in tissue from AD subjects. Furthermore, BChE activity is found to be associated only with the compact plaques.
More treatment and imaging strategies are concentrated on AChE because this is the enzyme involved in the synaptic function. However, the AChE activity declines in the progressing AD (AChE is lost early by up to 85% in specific AD brain regions (Perry et al. (1978) Neuropathol. Appl. Neurobiol., 4:273-7; Perry et al. (1980) Age Ageing., 9:9-16)) whereas the activity of BChE progressively increases as the severity of dementia advances (Atack et al. (1987) J. Neurochem., 48:1687-92). Thus, it is expected that BChE is better suited as the marker of the AD progression and responses to treatment. The ratio of BChE to AChE increases from within the range of about 0.2-0.5 in normal brain to as high as 11 in regions affected by AD (Giacobini, E. (2001) Drugs Aging, 18:891-8; Giacobini, E. (2003) Int. J. Geriatr. Psychiatry, 18:S1-S5). Advanced plaques show >93% BChE activity, compared with <20% in early diffuse plaques (Perry et al. (1978) Neuropathol. Appl. Neurobiol., 4:273-7; Perry et al. (1980) Age Ageing., 9:9-16; Guillozet et al. (1997) Ann. Neurol., 42:909-18; Mesulam et al. (1994) Ann. Neurol., 36:722-7) suggesting that these prominent longitudinal changes in the BChE activity in plaques are the ideal indicator for the AD staging and for the evaluation of effects of therapeutic interventions.
To date, compounds with the consistent history of effectiveness in treating the cognitive and functional symptoms of AD are cholinesterase inhibitors (Lahiri et al. (2004) Curr. Pharm. Des., 10:3111-9; Giacobini et al. (2002) J. Neural. Transm., 109:1053-65; Weinstock et al. (2006) J. Neural. Transm. Suppl., 70:443-6; Gauthier et al. (2006) Curr. Med. Res. Opin., 22:2251-65; Raschetti et al. (2005) Eur. J. Clin. Pharmacol., 61:361-8; Lopez-Pousa et al. (2005) Dement. Geriatr. Cogn. Disord., 19:189-95; Birks, J. (2006) Cochrane Database Syst Rev., 1:CD005593; Wilkinson et al. (2002) Int. J. Clin. Pract., 56:441-6.). In the majority of clinical trials conducted to date (see Birks, J. (2006) Cochrane Database Syst Rev., 1:CD005593 for review), the outcome is typically evaluated using the Clinician's Interview-Based Impression of Change scale (CIBIC-Plus), the Gottfries, Brane and Steen scale (GBS) or the Global Deterioration Scale (GDS) for the global assessment. Similarly, the cognitive and the daily activity assessments are done using several of the available impairment evaluation methods, all of which are descriptive and carry the risk of some degree of subjectivity. Concerns such as this instigated research into the noninvasive imaging methods that can quantify changes occurring in the AD brain as it deteriorates or responses to the therapeutic intervention (Irie et al. (1996) J. Nucl. Med., 37:649-655; Kilbourn et al. (1996) Synapse, 22:123-131; Kuhl et al. (1996) J. Nucl. Med., 37:21P; Iyo et al. (1997) Lancet, 349:1805-1809; Bencherif et al. (2002) Synapse, 45:1-9; Reed et al. (1999) Neurology, 52:680-682; Herholz et al. (2000) J. Neural Transm., 107:1457-68; Snyder et al. (2001) J. Cereb. Blood Flow Metab., 21:132-43; Brown-Proctor et al. (1999) Nucl. Med. Biol., 26:99-103; Johnson, K. A. (2006) Curr. Neurol. Neurosci. Rep., 6:496-503). A promising series of benzothiazole derivatives for imaging of amyloid deposits has been recently developed for PET and SPECT imaging (Wang et al. (2004) J. Mol. Neurosci., 24:55-62). Most of the imaging agents designed and tested to date target either amyloid plaques or are substrates for AChE. Because the cerebral amyloidosis precedes AD and does not appear to correlate with clinical or pathological criteria of AD (Wegiel et al. (2007) Acta Neuropathol (Berl)), imaging agents designed to visualize amyloid plaques may not be the best of candidates for imaging of the AD progression. For the same reason these agents are also probably not a good choice as the method to monitor effects of therapy. Radioactive drugs such as for example Pittsburgh Compound-B (Klunk et al. (2004) Ann. Neurol., 55:306-19; U.S. Pat. No. 7,270,800) or FDDNP (Small et al. (2006) N. Engl. J. Med., 355:2652-63) can differentiate between the AD brain and the brain of older individuals with normal cognitive function, even individuals with the mild cognitive impairment, by showing more binding to the brains of patients with AD than in healthy people. However, imaging of the AD progression in a specific patient during the anti-AD therapy using these imaging agents is not expected to be informative.
From the foregoing discussion, it will be appreciated that one of the major challenges in the development of therapeutic strategies to treat AD is the lack of objective, noninvasive methods that can accurately assess the status of the disease before, during and after the treatment.